Non-invasive delivery of protein and peptide therapeutics has been a long-standing objective in pharmaceutical development. Taking diabetes for example, to avoid the lifetime long frequent injection, the scientists in the field have contributed extensive research efforts over half century to examine variety of non-injective methods, comprising the inhalation, oral, nasal spray, needle-free injection, as well as transdermal delivery systems. However, non-injection delivery of protein and peptide medicines across our natural biological barriers remains to be a daunting task.
The invention of microneedles, an array of needles several hundreds micron in length, has provided a promising solution for cross-skin drug delivery. The tiny needles may penetrate the most impermeable layer of skin (stratum corneum) to create diffusion channels for lipophobic molecules without causing skin injury and pain feeling. There are four types of microneedle systems available to date, inorganic solid microneedles, metal hollow microneedles, polymeric dissolvable microneedles, and polymeric swellable microneedles. Among these four systems, only the swellable microneedles are feasible for efficient transdermal delivery of proteins and peptides. Solid microneedles lack a place to load drugs and a diffusion path for loaded drugs to pass through. Although coating medicines on the surface of the needle tips may offer an alternative, the loading capacity is small (approximately 300 ng per needle tip), and moreover, adsorption on metal surface often results in protein denaturing. Metal hollow microneedles, made by deposition of metal vapors onto solid microneedle tamplate, suffer from poor mechanic strength and low production efficiency. Polymeric dissolvable microneedles are actively studied for delivering vaccines, a kind of medication requires limited administration per year. For transdermal delivery of insulin, a drug requiring multiple doses per day, dissolvable microneedles are unflavored for the deposition of needle tips materials in the skin. Swellable microneedles are those which are hard and strong enough to penetrate the epidermis layer at dry state, but convert to swollen by absorbing the body fluid in the dermis layer. Hydration of the matrix of the tips of the swellable microneedles enables proteins or peptide pre-loaded in the microneedles to be released across the epidermis. We name the swellable microneedles as “phase-transition microneedles”.
For the microneedles to maintain their shape upon hydration so that they can be withdrawn from the skin without depositing themselves in the skin, the polymeric chains that form the needle matrix must be cross-linked. There are three conceivable mechanisms to cross-link the polymer chains, by covalent bonding, by ionic interaction with multiply charged ions, and by forming nano-crystalline domain as the cross-linking junctions. Covalent bonding method is associated with safety concerns for its involvement of in situ chemical reaction in the presence of medicines after the microneedles are formed. The ionic cross-linking does not create microneedles strong enough to withdraw at hydrated state. In addition, multiply charged ions may also possibly denature proteins. The cross-linking mechanism by formation of nano-crystalline domain is only seen in limited polymeric materials. However, it offers sufficient mechanic strength for the microneedles to complete withdraw from the skin at fully hydrated state. Moreover, the nano-crystalline cross-linking junctions are formed simply by a freeze-thaw treatment, a mild operation to delicate proteins.
This invention demonstrates the structure of a phase-transition microneedle patch and a process to fabricate this microneedle patch by cross-linking the polymer matrix through formation of nano-crystalline domains as the cross-linking junctions.